2. Academic Validation
  3. Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence

Chromosome 1q21.3 amplification is a trackable biomarker and actionable target for breast cancer recurrence

  • Nat Med. 2017 Nov;23(11):1319-1330. doi: 10.1038/nm.4405.
Jian Yuan Goh 1,  Min Feng 1,  Wenyu Wang 1,  Gokce Oguz 1 2,  Siti Maryam J M Yatim 1,  Puay Leng Lee 1,  Yi Bao 1,  Tse Hui Lim 3,  Panpan Wang 4,  Wai Leong Tam 1 5,  Annette R Kodahl 6,  Maria B Lyng 7,  Suman Sarma 1,  Selena Y Lin 8,  Alexander Lezhava 1,  Yoon Sim Yap 9,  Alvin S T Lim 3,  Dave S B Hoon 8,  Henrik J Ditzel 6 7,  Soo Chin Lee 5 10,  Ern Yu Tan 11 12,  Qiang Yu 1 2 4 13
Affiliations

Affiliations

  • 1 Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
  • 2 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
  • 3 Cytogenetics Laboratory, Department of Pathology, Singapore General Hospital, Singapore.
  • 4 Cancer Research Institute and School of Pharmacy, Jinan University, Guangzhou, China.
  • 5 Cancer Science Institute of Singapore, National University of Singapore, Singapore.
  • 6 Department of Oncology, Odense University Hospital, Odense, Denmark.
  • 7 Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
  • 8 Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, California, USA.
  • 9 Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
  • 10 Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore.
  • 11 Department of General Surgery, Tan Tock Seng Hospital, Singapore.
  • 12 Institute of Molecular and Cellular Biology, A*STAR, Biopolis, Singapore.
  • 13 Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.
PMID: 28967919 DOI: 10.1038/nm.4405
Abstract

Tumor recurrence remains the main reason for breast cancer-associated mortality, and there are unmet clinical demands for the discovery of new biomarkers and development of treatment solutions to benefit patients with breast Cancer at high risk of recurrence. Here we report the identification of chromosomal copy-number amplification at 1q21.3 that is enriched in subpopulations of breast Cancer cells bearing characteristics of tumor-initiating cells (TICs) and that strongly associates with breast Cancer recurrence. Amplification is present in ∼10-30% of primary tumors but in more than 70% of recurrent tumors, regardless of breast Cancer subtype. Detection of amplification in cell-free DNA (cfDNA) from blood is strongly associated with early relapse in patients with breast Cancer and could also be used to track the emergence of tumor resistance to chemotherapy. We further show that 1q21.3-encoded S100 calcium-binding protein (S100A) family members, mainly S100A7, S100A8, and S100A9 (S100A7/8/9), and IL-1 receptor-associated kinase 1 (IRAK1) establish a reciprocal feedback loop driving tumorsphere growth. Notably, this functional circuitry can be disrupted by the small-molecule kinase inhibitor pacritinib, leading to preferential impairment of the growth of 1q21.3-amplified breast tumors. Our study uncovers the 1q21.3-directed S100A7/8/9-IRAK1 feedback loop as a crucial component of breast Cancer recurrence, serving as both a trackable biomarker and an actionable therapeutic target for breast Cancer.

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  • HY-16379
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